The present invention relates to compounds of formula 
having valuable CNS, learning and memory forming pharmacological properties.
Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Therapeutic indications for NMDA NR-2B receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, ALS (amyotrophic lateral sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, depression and chronic and acute pain.
The present invention is directed to novel imidazole derivatives of formula 
wherein
A is phenyl, pyridin-2-yl, pyridin-3-yl, or piperidin-1-yl;
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, cycloalkyl, lower alkenyl, trifluoromethyl, xe2x80x94O-trifluoromethyl, xe2x80x94S-trifluoromethyl, S-lower alkyl, lower alkoxy, xe2x80x94CHF2, xe2x80x94C(lower alkyl)F2, xe2x80x94OCHF2, phenyl, nitro, benzyloxy, hydroxy and amino, or alternatively, R1 and R2 together with the carbon atoms to which they are attached in any adjacent positions, form a group selected from xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CF2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 and xe2x80x94CH2CH2xe2x80x94Oxe2x80x94;
R3 is selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, phenyl, S-lower alkyl, amino, lower alkyl-amino, xe2x80x94NHC(O)-lower alkyl and hydroxy-lower alkyl;
R4 and R5 are each independently selected from hydrogen and lower alkyl, or alternatively, R4 and R5 together with the carbon atoms to which they are attached form the group xe2x80x94(CH2)4xe2x80x94;
R6 and R6xe2x80x3 are each independently selected from hydrogen and lower alkyl;
X is xe2x80x94N less than  or 
Y is xe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90;
Z is xe2x80x94CR7xe2x95x90, xe2x80x94Nxe2x95x90, xe2x80x94NR7xe2x80x94, xe2x80x94Nxe2x95x90CR7xe2x80x94, xe2x95x90CHxe2x80x94Nxe2x95x90C(R7)xe2x80x94 or xe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94;
R7 is hydrogen, xe2x80x94CH2OH or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1; and
the dotted line may be 1, 2 or 3 bonds;
and to pharmaceutically acceptable acid addition salts thereof.
The heterocyclic aromatic group 
in formula I may have the following structure: 
Thus, by way of example, the following type of compounds are encompassed by formula I: 
wherein substituents are as described above.
The novel compounds of the invention and their salts have valuable therapeutic properties. Compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
Objects of the invention are the compounds of formula I and pharmaceutically acceptable acid addition salts thereof, the preparation of the compounds of formula I and salts thereof, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, and the use of the compounds of formula I and their pharmaceutically acceptable salts in the control or prevention of NMDA-mediated disorders.
The present invention embraces racemic mixtures and all their corresponding enantiomers.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. Preferred lower alkyl groups contain from 1 to 4 carbon atoms.
As used herein, the term xe2x80x9clower alkenylxe2x80x9d denotes a C2-C7 carbon group, having at least one double bond in the chain.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residue is as defined above and the alkyl group is connected to the remainder of the molecule via an oxygen atom.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a carbon ring with 3 to 6 carbon atoms, preperred is cyclopropyl.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of formula I are those wherein A is phenyl, for example the following group of compounds: 
wherein
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl, trifluoromethyl, S-lower alkyl, lower alkoxy, xe2x80x94OCHF2, phenyl, nitro, benzyloxy, hydroxy and amino, or alternatively, R1 and R2 together with the carbon atoms to which they are attached form a group selected from xe2x80x94(CH2)3xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 and xe2x80x94CH2CH2xe2x80x94Oxe2x80x94;
R3 is selected from the group consisting of hydrogen, lower alkyl, phenyl, S-lower alkyl, amino, lower alkyl-amino, xe2x80x94NHC(O)-lower alkyl and hydroxy-lower alkyl;
R4 and R5 are each independently selected from hydrogen and lower alkyl, or alternatively, R4 and R5 together with the carbon atoms to which they are attached form the group xe2x80x94(CH2)4xe2x80x94;
R6 and R6xe2x80x2 are each independently selected from hydrogen and lower alkyl;
X is xe2x80x94N less than  or 
Y is xe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90;
Z is xe2x80x94CR7xe2x95x90, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90CR7xe2x80x94, xe2x95x90CHxe2x80x94Nxe2x95x90C(R7)xe2x80x94 or xe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94;
R7 is hydrogen or lower alkyl;
n is 0, 1 or 2;
m is 0 or 1; and
the dotted line may be 1, 2, or 3 bonds;
and pharmaceutically acceptable acid addition salts thereof.
Especially preferred compounds of formula 
in the scope of the present formula I are those, wherein A is phenyl, R1 and R2 are each independently selected from lower alkyl, xe2x80x94CHF2, xe2x80x94C(lower alkyl)F2, CF3 and halogen, or alternatively, R1 and R2 together with the corresponding carbon atoms to which they are attached form the group xe2x80x94(CH2)3xe2x80x94; R3 is lower alkyl or amino; and R4, R5 R6, and R6xe2x80x2 are hydrogen. Examples of such compounds are:
1H-imidazole, 1-[[1-(4-chloro-3-methylphenyl)-1H-imidazol-4-yl]methyl]-2-ethyl-;
1H-imidazole, 1-[[1-(4-chloro-3-methylphenyl)-1H-imidazol-4-yl]methyl]-2-methyl-;
1H-imidazole, 1-[[1-(2,3-dihydro-1H-inden-5-yl)-1H-imidazol-4-yl]methyl]-2-methyl-;
1H-imidazole, 1-[[1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]methyl]-2-methyl;
1-[1-(4-chloro-3-methyl-phenyl)-1H-imidazol-4-yl-methyl]-1H-imidazol-2-yl-amine;
1H-imidazole, 1-[[1-[3-(1,1-difluoroethyl)phenyl]-1H-imidazol-4-yl]methyl]-2-methyl-;
1H-imidazole, 1-[[1-(3-difluoromethyl-4-fluorophenyl)-1H-imidazol-4-yl]methyl]-2-methyl-; and
1H-imidazole, 1-[[1-[3-(1,1-difluoroethyl)-4-fluorophenyl]-1H-imidazol-4-yl]methyl]-2-methyl-.
Further preferred are compounds of formula 
in the scope of the present formula I, wherein A is phenyl, R1 and R2 are each independently selected from halogen; R3 is lower alkyl or hydrogen; and R4, R5, R6, and R6xe2x80x2 are hydrogen. An Example of such a compound is:
1-(3,4-dichloro-phenyl)-3-(2-methyl-imidazol-1-yl-methyl)-1H-pyrazole.
Further preferred are compounds of formula 
in the scope of the present formula I, wherein A is phenyl, R1 and R2 are independently selected from halogen; R3 is lower alkyl or hydrogen; and R4, R5, R6, and R6xe2x80x2 are hydrogen. Examples of such compounds are:
1-(3,4-dichloro-phenyl)-4-imidazol-1-yl-methyl-1H-pyrazole; and
1-(3,4-dichloro-phenyl)-4-(2-methyl-imidazol-1-yl-methyl)-1H-pyrazole.
Further preferred are compounds of formula 
in the scope of the present formula I, wherein A is phenyl, R1 and R2 are independently selected from halogen, hydrogen, CF3 or lower alkyl; R3 is lower alkyl or hydrogen; and R4, R5, R6, R6xe2x80x2, and R7 are hydrogen. Examples of such compounds are:
1H-imidazole, 2-methyl-1-[[4-[3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]methyl]-,
1H-imidazole, 1-[[4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl]methyl]-2-methyl-;
1H-imidazole, 1-[[4-(3,4-difluorophenyl)-1H-imidazol-2-yl]methyl]-2-methyl-; and
1H-imidazole, 4-(4-fluoro-3-methylphenyl)-2-(1H-imidazol-1-yl-methyl)-.
Further preferred are compounds of formula 
in the scope of the present formula I, wherein A is phenyl, R1 and R2 are each independently selected from lower alkyl, halogen and CF3; R3 is lower alkyl or hydrogen; and R4, R5 R6, and R6xe2x80x2 are hydrogen. Examples of such compounds include:
3-(3,4-dimethyl-phenyl)-5-(2-methyl-imidazol-1-yl-methyl)-pyridine;
3-(4-fluoro-3-methyl-phenyl)-5-(2-methyl-imidazol-1-yl-methyl)-pyridine;
3-(4-chloro-3-methyl-phenyl)-5-(2-methyl-imidazol-1-yl-methyl)-pyridine;
3-(3-chloro-4-fluoro-phenyl)-5-(2-methyl-imidazol-1-yl-methyl)-pyridine; and
3-(4-chloro-3-trifluoromethyl-phenyl)-5-(2-methyl-imidazol-1-yl-methyl)-pyridine.
Further preferred are compounds of formula 
in the scope of the present formula I, wherein A is phenyl, R1 and R2 are each independently selected from halogen; R3 is lower alkyl; and R4, R5, R6, and R6xe2x80x2 are hydrogen. An example of such compound is:
4-(3,4-dichloro-phenyl)-2-(2-methyl-imidazol-1-yl-methyl)-pyridine.
Further preferred are compounds of formula 
in the scope of the present formula I, wherein A is phenyl, R1 and R2 are each independently selected from halogen; R3 is lower alkyl; and R4, R5, R6, and R6xe2x80x2 are hydrogen. An example of such compound is:
2-(3,4-dichloro-phenyl)-4-(2-methyl-imidazol-1-yl-methyl)-pyridine.
Further preferred compounds of formula I are those wherein A is pyridin-2- or 3-yl or piperidin-1-yl.
The afore-mentioned compounds of formula I can be manufactured in accordance with the invention by
a) reacting a compound of formula 
with a compound of formula 
to give a compound of formula 
xe2x80x83wherein A is phenyl or pyridin-2 or 3-yl, R1-R7 have the meanings given above and hal is Br or Cl, or
b) cleaving off a N-protecting group from a compound of formula 
to obtain a compound of formula 
xe2x80x83wherein A and R1-R6 have the meanings given above and P is a N-protecting group such as a 2-(trimethylsilyl)-ethoxymethyl group, or
c) reacting a compound of formula 
with a compound of formula 
to give a compound of formula 
xe2x80x83wherein A is phenyl or pyridin-2 or 3-yl, R1-R6 have the meanings given above and hal is Cl or Br, and
if desired, converting the compound of formula I thus obtained into a pharmaceutically acceptable salt by conventional methods known to one skilled in the art.
In the following the preparation of compounds of formula I are described in more detail:
In accordance with the process variants, described above, and with schemes 1-10, described below, compounds of formula I may be prepared by known procedures, for example the following:
In accordance with process step a), sodium hydride is added to a solution of an imidazole compound of formula V, for example 2-propylimidazole, 2-methylimidazole, imidazole, 4-methylimidazole or 4,5,6,7-tetrahydrobenzimidazole, in DMF. After 30 min. at room temperature the mixture is cooled in an ice bath and a compound of formulas II, III or IV, for example 4-chloromethyl-1-(3,4-dichloro-phenyl)-1H-imidazole, 4-chloromethyl-1-(3,4-dichloro-phenyl)-1H-pyrazole or 4-chloromethyl-1-(3,4-dichloro-phenyl)-3-methyl-1H-imidazole is added. The resulted mixture is stirred for 30 min. at room temperature and after evaporation of the solvent the compounds of formulas Ia, Ib and Ic are obtained in conventional manner.
Compounds of formulas Id may be prepared in accordance with reaction variant b). A compound of formula VI, for example 1H-imidazole, 2-[(2-methyl-1H-imidazol-1-yl)methyl]-4-[3-(trifluoromethyl)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]or 1H-imidazole, 4-(4-fluoro-3-methylphenyl)-[(2-methyl-1H-imidazol-1-yl)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl] is dissolved in EtOH and treated with HCl. Then the reaction mixture is refluxed overnight, cooled to room temperature, concentrated and purified.
Compounds of formulas If, Ig or Ih are prepared in accordance with reaction variant c) as follows: To a suspension of sodium hydride in mineral oil and DMF is added a compound of formula V, for example 2-propylimidazole, 2-methylimidazole, imidazole or 4-methylimidazole. This mixture is stirred for 1.5 hours at room temperature. Then a compound of formulas VIII, IX or X and triethylamine are added and the mixture is heated to about 100xc2x0 C. for 4 hours. After cooling the DMF is evaporated and the residue is directly chromatographed.
Pharmaceutically acceptable salts can be manufactured according to methods which are known per se and familiar to any person skilled in the art. The acid addition salts of compounds of formula I are especially well suited for pharmaceutical use.
In the following schemes 1-10 are described processes for preparation of compounds of formula I, starting from known compounds, from commercial products or from compounds, which can be prepared in conventional manner.
The preparation of compounds of formula I are described in more detail in working examples 1-233 below. 
The substituents R1 to R5 are described above and THF is tetrahydrofuran. In the compounds of formula XI the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula Ia.
Or, alternatively, compounds of formula XIV may be prepared 
wherein R1 and R2 are described above and DIBAH is diisobutylaluminium hydride and LAH is lithium aluminium hydride. 
The substituents R1 to R5 and R7 are described above and LAH is lithium aluminium hydride.
In the compounds of formula XV the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula Ia. 
The substituents R1 to R5 are described above and NBS is N-bromosuccinimide and AIBN is azo-bis-isobutyronitrile.
In the compounds of formula XX the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula Ib. 
The substituents R1 to R5 are described above and THF is tetrahydrofuran.
In the compounds of formula XXIII the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula Ic. 
The substituents R1 to R5 are described above and DMF is N,N-dimethylformamide.
In the compounds of formula XV the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula Id. 
The substituents R1 to R5 and R7 are described above and LAH is lithium aluminium hydride. Alternatively, the compound of formula XV may be replaced by the compound 
In the compounds of formula XV the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula Ie. 
The substituents R1 to R5 are described above.
In the compounds of formula XV the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula If. 
The substituents R1 to R5 are described above and LAH is lithium aluminium hydride.
In the compounds of formula XV the phenyl group may be replaced by the pyridin 2- or 3-yl groups to obtain the corresponding compounds of formula Ig. 
The substituents are described above and BINAP is 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl. 
In the compounds of formula XV or of the alternative compound the phenyl group may be replaced by the pyridin 2- or 3-yl groups.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable acid addition salts possess valuable pharmacodynamic properties. They are NMDA-receptor subtype 2B selective blockers, which have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation.
The compounds were investigated in accordance with the test given hereinafter.
Test Method
3H[R-(R*,S*)]-xcex1-(4-Hydroxy-phenyl)-xcex2-methyl-4-(phenyl-methyl)-1-piperidine propanol) Binding
Male Fxc3xcllinsdorf albino rats weighing between 150-200 g were used. Membranes were prepared by homogenization of the whole brain minus cerebellum and medulla oblongata with a Polytron (10.000 rpm, 30 seconds), in 25 volumes of a cold Tris-HCl 50 mM, EDTA 10 mM, pH 7.1 buffer. The homogenate was centrifuged at 48,000 g for 10 minutes at 4xc2x0 C. The pellet was resuspended using the Polytron in the same volume of buffer and the homogenate was incubated at 37xc2x0 C. for 10 minutes. After centrifugation the pellet was homogenized in the same buffer and frozen at xe2x88x9280xc2x0 C. for at least 16 hours but not more than 10 days. For the binding assay the homogenate was thawed at 37xc2x0 C., centrifuged and the pellet was washed three times as above in a Tris-HCl 5 mM, pH 7.4 cold buffer. The final pellet was resuspended in the same buffer and used at a final concentration of 200 mg of protein/ml.
3H-Ro 25-6981 binding experiments were performed using a Tris-HCI 50 mM, pH 7.4 buffer. For displacement experiments 5 nM of 3H-Ro 25-6981 were used and non specific binding was measured using 10 mM of tetrahydroisoquinoline and usually it accounts for 10% of the total. The incubation time was 2 hours at 4xc2x0 C. and the assay was stopped by filtration on Whatmann GF/B glass fiber filters (Unifilter-96, Packard, Zxc3xcrich, Switzerland). The filters were washed 5 times with cold buffer. The radioactivity on the filter was counted on a Packard Top-count microplate scintillation counter after addition of 40 mL of microscint 40 (Canberra Packard S.A., Zxc3xcrich, Switzerland).
The effects of compounds were measured using a minimum of 8 concentrations and repeated at least once. The pooled normalized values were analyzed using a non-linear regression calculation program which provide IC50 with their relative upper and lower 95% confidence limits.
The IC50 (xcexcM) of preferred compounds of formula I, tested in accordance with the above mentioned methods, is  less than 0.1 xcexcM. In the table below are shown some data for binding activity:
The compounds of formula I and their salts, as herein described, can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral application with the usual pharmaceutical adjuvant materials, for example, organic or inorganic inert carrier materials, such as, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene-glycols and the like. The pharmaceutical preparations can be employed in a solid form, for example, as tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. Pharmaceutical adjuvant materials can be added and include preservatives stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or to act as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in the range of about 0.1 mg per dosage to about 1000 mg per day of a compound of formula I although the upper limit can also be exceeded when this is shown to be indicated.
The following examples illustrate the present invention in more detail. However, they are not intended to limit its scope in any manner. All temperatures are given in degree Celsius.